Mutation-, aging-, and gene dosage-dependent accumulation of neuroserpin (G392E) in endoplasmic reticula and lysosomes of neurons in transgenic mice.
Mutations in human neuroserpin gene cause an autosomal dementia, familial encephalopathy with neuroserpin inclusion bodies (FENIB). We generated and analyzed transgenic mice expressing high levels of either FENIB-type (G392E) or wild-type human neuroserpin in neurons of the central nervous system. G392E neuroserpin accumulated age-dependently in neurons of the neocortex, thalamus, amygdala, pons, and spinal cord of homozygous transgenic mice. Such accumulations were not observed in hemizygous transgenic mice nor in transgenic mice for wild-type neuroserpin. In differential centrifugation of brain homogenates, G392E neuroserpin recovered in the nucleus-rich fraction dramatically increased along with aging, suggesting that the aggregations gradually increase their densities presumably by their conversion into heavier and more compact configurations. In immunoelectron microscopical analyses, immunopositivities for G392E neuroserpin were found not only in endoplasmic reticulum but also in lysosomes. G392E neuroserpin transgenic mice were much more susceptible to seizures induced by kainate administration than nontransgenic mice. Overall, G392E neuroserpin accumulated in the central nervous system neurons of transgenic mice in mutation-, aging-, and gene dosage-dependent manners. The established transgenic mice will be valuable to elucidate not only mechanisms for the formation of G392E neuroserpin aggregations but also pathways for the degradation and/or clearance of the already formed aggregations in neurons.
Takasawa
Akira
A
Department of Biochemistry, University of Toyama, Graduate School of Medicine and Pharmaceutical Sciences, 2630 Sugitani, Toyama 930-0194, Japan.
Kato
Ichiro
I
Takasawa
Kumi
K
Ishii
Yoko
Y
Yoshida
Toshiko
T
Shehata
Mohammad H
MH
Kawaguchi
Hiroshi
H
Mohafez
Omar M M
OM
Sasahara
Masakiyo
M
Hiraga
Koichi
K
D000375:Aging / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D019943:Amino Acid Substitution; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000648:ultrastructure; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism / Q000648:ultrastructure; D003704:Dementia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000378:metabolism* / Q000648:ultrastructure; D018690:Excitatory Amino Acid Agonists / Q000009:adverse effects / Q000494:pharmacology; D018628:Gene Dosage; D030342:Genetic Diseases, Inborn / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D002479:Inclusion Bodies / Q000235:genetics / Q000378:metabolism / Q000648:ultrastructure; D007608:Kainic Acid / Q000009:adverse effects / Q000494:pharmacology; D008247:Lysosomes / Q000235:genetics / Q000378:metabolism* / Q000648:ultrastructure; D051379:Mice; D008822:Mice, Transgenic; D020125:Mutation, Missense; D009474:Neurons / Q000378:metabolism* / Q000648:ultrastructure; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism*; D012640:Seizures / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015843:Serpins / Q000235:genetics / Q000378:metabolism*; D013116:Spinal Cord / Q000378:metabolism / Q000648:ultrastructure; D000097522:Neuroserpin
D018690:Excitatory Amino Acid Agonists; D007608:Kainic Acid; D009479:Neuropeptides; D015843:Serpins; D000097522:Neuroserpin